Chrysene derivatives

ABSTRACT

The present invention relates to compounds of formula (I) 
     
         ArCH.sub.2 R.sup.1                                         (I) 
    
     or a monomethyl or a monoethyl ether thereof (the compound of formula (I) including these ethers may contain no more than 30 carbon atoms in total); ethers, esters thereof; acid addition salts thereof; wherein Ar is a chrysene or substituted chrysene ring system; R 1  contains not more than eight carbon atoms and is a group ##STR1## wherein m is 0 or 1; 
     R 5  is hydrogen; 
     R 6  and R 7  are the same or different and each is hydrogen or C 1-3  alkyl optionally substituted by hydroxy; 
     R 8  and R 9  are the same or different and each is hydrogen or C 1-3  alkyl; ##STR2##  is a five- or six-membered saturated carbocyclic ring; R 10  is hydrogen, methyl or hydroxymethyl; 
     R 11 , R 12  and R 13  are the same or different and each is hydrogen or methyl; 
     R 14  is hydrogen, methyl, hydroxy, or hydroxymethyl.

This is a divisional of co-pending Ser. No. 662,379 filed on Oct. 18,1984, now U.S. Pat. No. 4,719,046, which is a continuation-in-part ofSer. No. 495,512 filed May 17, 1983, abandoned.

The present invention relates to polycyclic aromatic alkanol derivativeswhich have been found to have biocidal activity. More specifically theinvention concerns aminoalkanol derivatives containing a polycarbocyclicaromatic ring system, methods for the synthesis thereof, pharmaceuticalformulations thereof, novel intermediates therefor, pharmaceuticalformulations thereof and the use thereof as biocidal agents,particularly antitumor agents.

Accordingly, in a first aspect, the present invention provides acompound of the formula (I)

    ArCH.sub.2 R.sup.1                                         (I)

or a monomethyl or monoethyl ether thereof (the compound of formula (I)including these ethers may contain no more than 30 carbon atoms intotal); ethers, esters thereof; acid addition salts thereof;

wherein

Ar is a chrysene ring optionally substituted by one or two substituents(the substituents will contain not more than four carbon atoms in totalwhen taken together being the same or different and are selected fromhalogen; cyano; C₁₋₄ alkyl or C₁₋₄ alkoxy, each optionally substitutedby hydroxy or C₁₋₂ alkoxy; halogen substituted C₁₋₂ alkyl or C₁₋₂alkoxy; a group S(O)_(n) R² wherein n is an integer 0,1 or 2 and R² isC₁₋₂ alkyl optionally substituted by hydroxy or C₁₋₂ alkoxy; or thechrysene ring is optionally substituted by a group NR³ R⁴ containing notmore than 5 carbon atoms wherein R³ and R⁴ are the same or different andeach is a C₁₋₃ alkyl group or NR³ R⁴ forms a five- or six-memberedheterocyclic ring optionally containing one or two additionalheteroatoms);

R¹ contains not more than eight carbon atoms and is a group ##STR3##wherein m is 0 or 1;

R⁵ is hydrogen;

R⁶ and R⁷ are the same or different and each is hydrogen or C₁₋₃ alkyloptionally substituted by hydroxy;

R⁸ and R⁹ are the same or different and each is hydrogen or C₁₋₃ alkyl;##STR4## is a five- or six-membered saturated carbocyclic ring; R¹⁰ ishydrogen, methyl or hydroxymethyl;

R¹¹, R¹² and R¹³ are the same or different and each is hydrogen ormethyl;

R¹⁴ is hydrogen, methyl, hydroxy, or hydroxymethyl.

Suitably ArCH₂ R¹ or a monomethyl or monethyl ether thereof contains notmore than 28 carbon atoms in total.

Ar is suitably 6-chrysenyl, ##STR5## suitably m is 0, suitably R¹ is##STR6## wherein R¹⁶ is CH₂ OH,CH(CH₃)OH or CH₂ CH₂ OH,

R¹⁷ is hydrogen, C₁₋₃ alkyl or CH₂ OH,

R¹⁸ is hydrogen or methyl.

Preferably R¹⁶ is CH₂ OH or CH(CH₃)OH; R¹⁷ is hydrogen, methyl, ethyl orCH₂ OH.

Most preferably R¹ is a diol of the structure ##STR7## wherein R¹⁹ ishydrogen or methyl and R²⁰ is hydrogen, methyl or ethyl, preferablymethyl.

Acid addition salts included within the scope of the present inventionare those of compound of formula (I) and ethers and esters thereof.

Esters and nonpharmaceutically useful acid addition salts of thecompounds of the formula (I) are useful intermediates in the preparationand purification of compounds of the formula (I) and pharmaceuticallyuseful acid addition salts thereof, and are therefore within the scopeof the present invention. Thus, acid addition salts of the compounds ofthe formula (I) useful in the present invention include but are notlimited to those derived from inorganic acids, such as hydrochloric,hydrobromic, sulfuric and phosphoric acids, and organic acids such asisethionic(2-hydroxyethylsulfonic), maleic, malonic, succinic,salicylic, tartaric, lactic, citric, formic, lactobionic, pantothenic,methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic,naphthalene-2-sulfonic, and ascorbic acids, and amino acids such asglycine.

Acid addition salts particularly useful as biocidal agents are thosethat are pharmacologically and pharmaceutically acceptable. Thus,suitable acid addition salts include but are not limited to thosederived from hydrochloric, methanesulfonic, ethanesulfonic, isethionic,lactic, and citric acids.

The preferred pharmacologically and pharmaceutically acceptable acidaddition salts are those that are soluble in solvents suitable forparenteral administration, for example, hydrochlorides,methanesulfonates and isethionates.

Esters of compounds of formula (I) are derived from acids known to thoseskilled in the art to be suitable for ester formation, and areconveniently those derived from C₁₋₆ alkanoic acids or alkanoic acidderivatives, for example acetic acid, propionic acid, n-butyric acid andiso-butyric acid. The esters may be formed from all or only some of thehydroxy groups contained in the compounds of formula (I). Specificcompounds within the scope of formula (I) include;

2-((6-Chrysenylmethyl)amino)-2-methyl-1-propanol,

2-((3-Chrysenylmethyl)amino)-2-methyl-1,3-propanediol,

2-((2-Chrysenylmethyl)amino)-2-methyl-1,3-propanediol,

2-((6-Chrysenylmethyl)amino)-2-methyl-1,3-propanediol,

2-((6-Chrysenylmethyl)amino)-2-hydroxymethyl-1,3-propanediol,

2-((6-Chrysenylmethyl)amino)-2-ethyl-1,3-propanediol,

(+-)(2R*,3R*)-2-((6-Chrysenylmethyl)amino)-2-methyl-1,3-butanediol,

(+-)(2R*,3S*)-2-((6-Chrysenylmethyl)amino)-2-methyl-1,3-butanediol,

2-((6-Chrysenylmethyl)amino)-2-ethoxymethyl-1,3-propanediol,

3-Methoxy-2-((6-chrysenylmethyl)amino)-2-methyl-1-propanol,

(1α,2β,3α)-2-((6-Chrysenylmethyl)amino)-1,3-cyclohexanediol,

2-((6-Chrysenylmethyl)amino)-2-isopropyl-1,3-propanediol,

2-((6-Chrysenylmethyl)amino)-2-methyl-1,4-butanediol,

(+-)(2R*,3RS*,4R*)-3-(6-Chrysenylmethyl)amino)-3-methyl-2,5-pentanediol,

meso-3-((6-Chrysenylmethyl)amino)-2,4-pentanediol,

2-((6-Chrysenylmethyl)amino)-1,3-propanediol,

2-(((12-Ethyl-6-chrysenyl)methyl)amino)-2-methyl-1,3-propanediol,

2-(((12-Chloro-6-chrysenyl)methyl)amino)-2-methyl-1,3-propanediol and

2-(((12-Ethoxy-6-chrysenyl)methyl)amino)-2-methyl-1,3-propanediol;ethers, esters thereof; acid addition salts thereof.

Of these specific examples of compounds of formula (I), the preferredcompounds are 2-((6-chrysenylmethyl)amino)-2-methyl-1,3-propanediol,(+-)(2R*,3R*)-2-((6-chrysenylmethyl)amino)-2-methyl-1,3-butanediol, and(+-)(2R*,3S*)-2-((6-chrysenylmethyl)amino)-2-methyl-1,3-butanediol;ethers, esters thereof; acid addition salts thereof.

Of these specific examples of compounds of formula (I), the mostpreferred compound is2-((6-chrysenylmethyl)amino)-2-methyl-1,3-propanediol; ethers, estersthereof; acid addition salts thereof.

The compounds of formula (I) and their ethers, esters and salts thereofmay be prepared by any method known in the art for the preparation ofcompounds of analogous structure. Thus, the compounds of formula (I)may, for example, be prepared by any of the methods defined below.

1. The reduction of a compound of formula (II) ##STR8## Wherein R¹ -R⁴are as hereinbefore defined or an appropriately protected derivativethereof followed by deprotection where appropriate.

The conditions and reagents for such a reaction are well known to thoseskilled in the art, and any such conditions/reagents may be employed.The conversion of (II) or suitably protected derivatives thereof may becarried out by a reducing agent followed by deprotection if necessary.The reduction is conveniently carried out by a metal hydride such aslithium aluminum hydride, sodium borohydride, sodium cyanoborohydride,or by catalytic hydrogenation, conveniently by hydrogen in the presenceof a metal catalyst such as palladium or platinum, or equivalentreagents as outlined by J. March, Advanced Organic Chemistry, 2nd ed.,pages 819-820, McGraw Hill, New York, 1977. The reduction is suitablycarried out with the compound of formula (II) in solution in an inertsolvent or mixture of solvents compatible with the reducing agent, at anon-extreme temperature, for example, between 0° and 80° C.,conveniently at room temperature.

In the case of lithium aluminum hydride and like reagents, suitablesolvents include ethers (for example tetrahydrofuran, diethyl ether and1,2-dimethoxyethane) optionally in the presence of a hydrocarboncosolvent (for example toluene, benzene or hexane).

In the case of sodium borohydride and like reagents, suitable solventsinclude alcohols (for example ethanol, methanol or isopropanol)optionally in the presence of a hydrocarbon cosolvent (for exampletoluene, benzene or hexane) or an ether cosolvent (for examplediethylether or tetrahydrofuran).

In the case of sodium cyanoborohydride and like reagents, suitablesolvents include those described for sodium borohydride and in thepresence of an acid conveniently glacial acetic acid or ethanolichydrochloric acid as outlined in, for example, R. Hutchins et al.,Organic Preparations and Procedures International 11, 201 (1979).

In the case of catalytic hydrogenation, suitable solvents includealcohols (for example methanol and ethanol) optionally in the presenceof a hydrocarbon cosolvent (for example toluene or benzene) or ethercosolvent (for example diethyl ether or tetrahydrofuran) in the presenceof an acid (for example glacial acetic acid or ethanolic hydrochloricacid) or in glacial acetic acid.

Protected derivatives of compounds of formula (II) are conveniently usedwhen lithium aluminum hydride is employed as the reducing agent.Convenient protecting groups are compatible with the reducing agentutilized and are readily removed under nondestructive conditions, forexample benzyl, tetrahydropyranyl and isopropylidene ethers.

It is often convenient not to isolate the compound of the formula (II)but to react a compound of the formula (III) with a compound of theformula (IV): ##STR9## wherein Ar and R¹ -R⁴ are as defined in (I), andreduce the compound of the formula (II) so formed in situ. The reactionof the compounds of the formulae (III) and (IV) is again suitablycarried out using conditions and reagents which are well known to thoseskilled in the art, for example in the presence of an acid, such as asulfonic acid, i.e. p-toluenesulfonic acid, in an appropriate inertsolvent, such as an aromatic hydrocarbon, suitably toluene, withazeotropic removal of water followed by treatment with the reducingagent in an appropriate solvent, suitably ethanol or methanol.Alternatively, (II) formed under equilibrium conditions in appropriatesolvents can be reduced in situ with an appropriate reducing agent,suitably sodium cyanoborohydride. The compound of formula (III) may bein the form of a protected aldehyde, for example an acetal, whichliberates the aldehyde function under the reaction conditions.

In turn, a compound of formula (III) can be synthesized by reacting theappropriate polycyclic aromatic hydrocarbon with a formylating agentsuch as that generated by the reaction between SnCl₄ and Cl₂ CHOCH₃ orequivalent reagents, for example, according to the method of A. Reicheet al., Chem. Ber. 93, 88 (1960), or with other standard formylatingreagents/procedures known to the art, for example, the Gatterman-Kochreaction (CO/HCl/AlCl₃ /CuCl), the Gatterman reaction (HCN/HCl/ZnCl₂),and the Vilsmeier reaction (POCl₃ /PhN(Me)CHO, or POCl₃ /Me₂ NCHO) (J.March, vide supra, pages 494-497).

The compounds of the formula (III) may also be prepared from anappropriate polycyclic aromatic hydrocarbon substituted by a suitablefunctional group such as CH₂ OH, CHBr₂, CH₃, COCH₃, COOH, or CN, andconverting this functional group to an aldehyde group by methods wellknown to those skilled in the art.

Where the polycyclic aromatic ring bears substituents, the compound offormula (III) may be prepared by a variety of methods known in the artof organic chemistry depending on the nature of the substituent on thepolycyclic ring. For example, if the substituent(s) is a halogen, thestarting materials may be prepared by direct treatment of the polycyclicaromatic hydrocarbon with a halogenating agent (e.g. Cl₂, Br₂, or SO₂Cl₂) or indirectly by such routes as the Sandmeyer reaction (H. H.Hodgson, Chem. Rev. 40, 251 (1947). If the substituent(s) is alkyl, thepolycyclic aromatic hydrocarbon may be reacted with the appropriatereagents under Friedel-Crafts reaction conditions (G. A. Olah, FriedelCrafts and Related Reactions, Vols. 1-3, Interscience, New York, NY,1963-1965).

The compounds of the formula (IV) also may be prepared by methods knownin the art, for example, by the reaction of compound NO₂ CH₂ R² with anappropriate aldehyde, conveniently acetaldehyde or formaldehyde (as inB. M. Vanderbilt and H. B. Hass, Ind. Eng. Chem. 32, 34 (1940)) followedby reduction (as outlined in J. March, vide supra, pages 1125-1126),conveniently by hydrogen and a metal catalyst (for example, a platinumcontaining catalyst) in an appropriate solvent, conveniently glacialacetic acid.

2. The reduction of a compound of the formula (V) ##STR10## wherein Arand R¹ -R⁴ are as hereinbefore defined and the hydroxy groups areoptionally protected, followed by deprotection of the hydroxy groupswhere appropriate. The reduction may be carried out by standard reducingagents known for carrying out this type of reduction (as outlined in J.March, vide supra page 1122), for example, a hydride reagent such aslithium aluminium hydride in an inert solvent, such as an ether, i.e.tetrahydrofuran, at a non-extreme temperature, for example, at between0° and 100° C. and conveniently at the reflux temperature of the ether.The compound of the formula (V) may be formed by the reaction of theappropriate acid (ArCOOH) or a suitable reactive acid derivative thereof(as outlined in J. March, vide supra, pages 382-390), for example, anacid halide, in an inert solvent with an amine of the formula (IV) inwhich the hydroxy groups are optionally protected, for example, when thecompound of the formula (IV) is a diol, by an isopropylidene group. Thecompound of the formula (V) so formed is suitably reduced in situ anddeprotected if necessary to give a compound of formula (I). Thecompounds of the formula ArCOOH can be prepared by methods well known tothose skilled in the art.

3. The reaction of a compound ArCH₂ L (wherein Ar is as hereinbeforedefined and L is a leaving group) with a compound of the formula (IV) ashereinbefore defined. Suitable leaving groups are those defined by J.March, vide supra, pages 325-331, and include halogens such as chlorineand bromine and sulfonic acid derivatives such as p-toluenesulfonate.The reaction is suitably carried out in an appropriate solvent, such asa dipolar aprotic solvent or alcohol at a non-extreme temperature, forexample 50°-100°. The compounds of the formula ArCH₂ L can be preparedby methods well known to those skilled in the art.

There is therefore provided, as a further aspect of the invention, amethod for the preparation of a compound of formula (I) comprising anymethod known for the preparation of analogous compounds, in particularthose methods defined in (1) to (3) hereinabove.

The compounds of this invention have biocidal activity, e.g. are toxicto certain living cells which are detrimental to mammals, for examplepathogenic organisms and tumor cells.

This toxicity to pathogenic organisms has been demonstrated by activityagainst viruses (e.g. Herpes simplex 1/vero), fungi (e.g. Candidaalbicans), protozoa (e.g. Eimeria tenella and Trichomonas vaginalis),bacteria (e.g. Mycoplasma smegmatis and Streptococcus pyogenes), andhelminths (e.g. Nippostrongylus brasiliensis). The antitumor activity ofcompounds of formula (I) has been demonstrated in a number of recognizedscreens and primarily by activity against ascitic P388/0 leukemia.

Preferred compounds of the formula (I) are those which have antitumoractivity. The activity against ascitic tumors, including P388/0, isevidenced by reduction of tumor cell number in mammals (for example,mice bearing ascitic tumors) and consequent increase in survivalduration as compared to an untreated tumor bearing control group.Antitumor activity is further evidenced by measurable reduction in thesize of solid tumors following treatment of mammals with the compoundsof this invention compared to the tumors of untreated control tumorbearing animals. Compounds of formula (I) are active against murinetumors such as lymphocytic leukemia P388/0, lymphocytic leukemia L1210,melanotic melanoma B16, P815 mastocytoma, MDAY/D2 fibrosarcoma, colon 38adenocarcinoma, M5076 rhabdomyosarcoma and Lewis lung carcinoma.

Activity in one or more of these tumor tests has been reported to beindicative of antitumor activity in man (A. Goldin et al. in Methods inCancer Research ed. V. T. DeVita Jr. and H. Busch, 16 165, AcademicPress, N.Y. 1979).

There are sublines of P388/0 which have been made resistant to thefollowing clinically useful agents: cytosine arabinoside, doxorubicin,cyclophosphamide, L-phenylalanine mustard, methotrexate, 5-fluorouracil,actinomycin D, cis-platin and bis-chloroethylnitrosourea. Compounds ofthis invention show potent activity against these drug-resistant tumorsusing the procedure for P388/0 above.

Compounds of formula (I) have also been found to be active against humantumor cells in primary cultures of lung, ovary, breast, renal, melanoma,unknown primary, gastric, pancreatic, mesothelioma, myeloma, and coloncancer. (As used herein "cancer" is to be taken as synonymous with"malignant tumor" or more generally "tumor" unless otherwise noted. )This is a procedure in which the prevention of tumor cell colonyformation, i.e. tumor cell replication, by a drug has been shown tocorrelate with clinical antitumor activity in man (D. D. Von Hoff etal., Cancer Chemotherapy and Pharmacology 6, 265 (1980); S. Salmon andD. D. Von Hoff, Seminars in Oncology, 8, 377 (1981)).

Compounds of formula I which have been found to have antitumor activityintercalate in vitro with DNA (this property is determined byviscometric methods using the procedure of W. D. Wilson et al., NucleicAcids Research 4, 2697 (1954)) and a log P as calculated by the methodof C. Hansch and A. Leo in Substituent Constants for CorrelationAnalysis in Chemistry and Biology, John Wiley and Sons, New York, 1979,lying in the range between -2.0 and +2.5.

As has been described above, the compounds of the present invention areuseful for the treatment of animals (including humans) bearingsusceptible tumors. The invention thus further provides a method for thetreatment of tumors in animals, including mammals, especially humans,which comprises the administration of a clinically useful amount ofcompound of formula (I) in a pharmaceutically useful form, once orseveral times a day or other appropriate schedule, orally, rectally,parenterally, or applied topically.

In addition, there is provided as a further, or alternative, aspect ofthe invention, a compound of formula (I) for use in therapy, for exampleas an antitumor agent.

The amount of compound of formula (I) required to be effective as abiocidal agent will, of course, vary and is ultimately at the discretionof the medical or veterinary practitioner. The factors to be consideredinclude the condition being treated, the route of administration, thenature of the formulation, the mammal's body weight, surface area, ageand general condition, and the particular compound to be administered. Asuitable effective antitumor dose is in the range of about 0.1 to about120 mg/kg body weight, preferably in the range of about 1.5 to 50 mg/kg,for example 10 to 30 mg/kg. The total daily dose may be given as asingle dose, multiple doses, e.g., two to six times per day, or byintravenous infusion for a selected duration. For example, for a 75 kgmammal, the dose range would be about 8 to 9000 mg per day, and atypical dose would be about 2000 mg per day. If discrete multiple dosesare indicated, treatment might typically be 500 mg of a compound offormula I given 4 times per day in a pharmaceutically usefulformulation.

While it is possible for the active compound (defined herein as compoundof formula (I), or ether, ester, or salt thereof) to be administeredalone, it is preferable to present the active compound in apharmaceutical formulation. Formulations of the present invention, formedical use, comprise an active compound together with one or morepharmaceutically acceptable carriers thereof and optionally othertherapeutical ingredients. The carrier(s) must be pharmaceuticallyacceptable in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof.

The present invention, therefore, further provides a pharmaceuticalformulation comprising a compound of formula (I) (in the form of thefree base, ether, or ester derivative or a pharmaceutically acceptableacid addition salt thereof) together with a pharmaceutically acceptablecarrier therefore.

There is also provided a method for the preparation of a pharmaceuticalformulation comprising bringing into association a compound of formula(I), an ether, ester, or pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier therefore.

While the antitumor activity of the compounds of formula (I) is believedto reside in the free base, it is often convenient to administer an acidaddition salt of a compound of formula (I).

The formulations include those suitable for oral, rectal or parenteral(including subcutaneous, intramuscular and intravenous) administration,Preferred are those suitable for oral or parenteral administration.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active compound intoassociation with a carrier which constitutes one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing the active compound into assocation with a liquidcarrier or a finely divided solid carrier or both and then, ifnecessary, shaping the product into desired formulations.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets, tablets orlozenges, each containing a predetermined amount of the active compound;as a powder or granules; or a suspension in an aqueous liquid ornon-aqueous liquid such as a syrup, an elixir, an emulsion or a draught.

A table may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets my be prepared bycompressing in a suitable machine the active compound in a free-flowingform such as a powder or granules, optionally mixed with a binder,lubricant, inert diluent, surface active or dispersing agent. Moldedtablets may be made by molding in a suitable machine, a mixture of thepowdered active compound with any suitable carrier.

A syrup may be made by adding the active compound to a concentrate,aqueous solution of a sugar, for example sucrose, to which may also beadded any accessory ingredients. Such accessory ingredient(s) mayinclude flavorings, an agent to retard crystallization of the sugar oran agent to increase the solubility of any other ingredient, such as apolyhydric alcohol for example glycerol or sorbitol.

Formulations for rectal administration may be presented as a suppositorywith a conventional carrier such as cocoa butter.

Formulations suitable for parenteral administration convenientlycomprise a sterile aqueous preparation of the active compound which ispreferably isotonic with the blood of the recipient. Such formulationssuitably comprise a solution of a pharmaceutically and pharmacologicallyacceptable acid addition salt of a compound of the formula (I) that isisotonic with the blood of the recipient. Thus, such formulations mayconveniently contain distilled water, 5% dextrose in distilled water orsilane and a pharmaceutically and pharmacologically acceptable acidaddition salt of a compound of the formula (I) that has an appropriatesolubility in these solvents, for example the hydrochloride, isethionateand methanesulfonate salts, preferably the latter.

Useful formulations also comprise concentrated solutions or solidscontaining the compound of formula (I) which upon dilution with anappropriate solvent give a solution suitable for parental administrationabove.

In addition to the aforementioned ingredients, the formulations of thisinvention may further include one or more accessory ingredient(s)selected from diluents, buffers, flavoring agents, binders, surfaceactive agents, thickeners, lubricants, preservatives (includingantioxidants) and the like.

The following examples are provided by the way of illustration of thepresent invention and should in no way be construed as a limitationthereof.

GENERAL COMMENTS

All solvents were reagent grade and used without further purificationwith the following exception. THF was dried by distillation from Na/Kalloy under nitrogen (N₂) and used immediately. Toluene (PhCH₃) wasdistilled from CaH₂ under N₂ and stored over 3 Å molecular sieves.Chemicals used were reagent grade and used without purification unlessnoted. The full name and address of the suppliers of the reagents andchemicals is given when first cited. After this, an abbreviated name isused.

Preparative HPLC was carried out on a Water's Prep LC/System 500Amachine using two 500 g silica gel (SiO₂) cartridges unless otherwisenoted. Plugs of SiO₂ used for purifications were "flash chromatography"SiO₂ (Merck & Co., Inc., Merck Chemical Division, Rahway, NJ, 07065,silica gel 60, 230-400 mesh). In this procedure, an appropriate volumesintered glass funnel was filled approximately 3/4 full with the SiO₂and packed evenly by tapping the outside of the funnel. A piece offilter paper was then placed on top of the SiO₂ and a solution of thematerial to be purified applied evenly to the top. Gentle suctionthrough a filter flask moved the eluting solvent through the plugrapidly. The appropriate size fractions were combined as needed andfurther manipulated.

General procedures are described in detail. Analogous procedures showmelting point (mp), recrystallization solvents, and elemental analyses(all elements analyzing within a difference of ≦0.4% of the expectedvalue). Any changes to the procedure such as solvent, reactiontemperature, reaction time, or workup are noted.

NMR (¹ H, ¹³ C), IR, MS data of all new products were consistent withthe expected and proposed structures. The positions assigned tostructural isomers were unequivocally determined by a number of NMRtechniques. All final products were dried in a vacuum oven at 20 mm Hgpressure at the temperature indicated overnight (12-16 h). Alltemperatures are in degrees Celsius. Other abbreviations used are: roomtemperature (RT), absolute (abs.), round bottom flask (RB flask),minutes (min), hours (h).

EXAMPLE 1 2-((6-Chrysenylmethyl)amino)-2-methyl-1,3-propanediol 1A.6-Chrysenecarbaldehyde

A 5 L 3-neck flask fitted with overhead mechanical stirrer, thermometer,condenser and N₂ line was charged with chrysene (Eastman Kodak Co.,Rochester, NY, 14650, 100 g, 0.438 mol) and o-dichlorobenzene (2.5 L).The liquid was warmed until all the large chunks of solid dissolved(80°) and then cooled quickly to give finely divided crystals. Afterfurther cooling with a salt-ice bath to 5°, SnCl₄ (Aldrich Chemical Co.,Milwaukee, WI, 53201, 98%, 228.2 g, 0.876 mol, 102.4 mL) was added inone portion. No temperature change occurred. The reaction mixture waskept below 5°, and 1,1-dichloromethylmethylether (Aldrich, 70.48 g,0.613 mol, 55.45 mL) was added dropwise over 1 h. The resultingsuspension was warmed slowly to 40°. The reaction mixture was thencooled to 10° and hydrolysed by careful addition of 1 L of cold H₂ O.After 4 h, the layers were separated and the organic layer filtered,dried with anhydrous Na₂ SO₄ (Mallinckrodt Co., St. Louis, MO, 63147,100 g) and filtered again. The clear yellow solution was split into 2portions and each passed through a 500 g plug of SiO₂ using PhCH₃ as theeluting solvent with 500 mL fractions. This chromatography separatedunreacted chrysene (3 g) from the aldehyde and a more polar product.Fractions containing the aldehyde were combined and the PhCH₃ removed.Crystals formed during this process and were removed periodically byfiltration. After drying (at 60°) the yield of 6-chrysenecarbaldehydewas 89.46 g (79.7%) mp 167°-169°, (C, H), (lit. 168°, N. P. Buu Hoi,J.-P. Hoffinger, and P. Jacquigon, Bull. Soc. Chim. Fr. 3808 (1968)).

1B. 2-((6-Chrysenylmethyl)amino)-2-methyl-1,3-propanediol hydrochloride

To a 2 L Erlenmeyer flask was added 6-chrysenecarbaldehyde (21.2 g, 82.7mmol), 2-amino-2-methyl-1,3-propanediol (Aldrich, 9.13 g, 86.8 mmol),p-toluenesulfonic acid.H₂ O (Eastman, 0.5 g, 2.5 mmol), and PhCH₃ (500mL). The mixture was warmed to reflux for a few minutes and H₂ O (2-3mL) was driven off. The resulting golden colored solution was allowed tocool to RT, diluted with abs. EtOH (500 mL) and stirred overnight. NaBH₃CN (Aldrich, 95%, 2.51 g, 42 mmol) was added to the reaction. After theNaBH₃ CN dissolved, an indicator (bromocresol green, Eastman, 5 mg) wasadded. To the resulting blue solution was added 5 drops of 1M ethanolicHCl every 15 min. After 3 days the indicator turned green then yellowand a voluminous white precipitate was present in the flask. To theflask was then added 1M ethanolic HCl (10 mL). The reaction was dilutedto 4 L with abs. Et₂ O and stirred for 1 h. The precipitate was thenfiltered through a medium porosity glass fritted funnel and pressed dry.The filter cake was washed thoroughly with 20% HCl (5×250 mL), presseddry and then washed with CH₂ Cl₂ (4×500 mL), pressed and sucked dry. Thesolid was dissolved in abs. EtOH (1400 mL). 1M ethanolic HCl (1 mL) and5 g of Calgon® (a trademark of Calgon Corporation, a subsidiary of Merckand Co., Pittsburgh, PA, 15230) brand of activated charcoal were added,and the mixture boiled and filtered through a pad of Celite® (atrademark of Johns Manville Co., P.O. Box 5108, Denver, CO, 80217) brandof filtered aid. The clear yellow solution was concentrated to 500 mLand diluted to 2 L with abs. Et₂ O which was then filtered to give thecrude product. Further crystallization (2×) from CH₃ OH/Et₂ O (1:3) gave18.07 g (57.2%) of 2-((6-chrysenylmethyl)amino)-2-methyl-1,3-propanediolhydrochloride mp 241°-243° (dec), (C, H, Cl, N).

1C. 2-((6-Chrysenylmethyl)amino)-2-methyl-1,3-propanediolmethanesulfonate

To a 12 L RB flask equipped with overhead stirrer, condenser,thermometer, and Dean-Stark trap was added chrysene-6-carbaldehyde(Cambridge Chemical, Inc., 202 E. Smith St., Milwaukee, WI, 53207, 260g, 1.01 mol), 2-amino-2-methyl-1,3-propanediol (Aldrich, 213 g, 2.03mol), p-toluenesulfonic acid monohydrate (Aldrich, 0.8 g, 0.104 mol) andPhCH₃ (3.8 L). The mixture was stirred at reflux with removal of H₂ Ofor 2 h (or until no H₂ O is collected). The mixture was cooled to RTand diluted with abs. EtOH (3.8 L). Solid NaBH₄ (MCB ManufacturingChemists, inc., 2909 Highland Ave., Cincinnati, OH, 45212, 46 g, 1.22mol) was added in portions to the stirred mixture with the temperaturemaintained at 25°-30° by external cooling. After the addition wascompleted, the reaction was stirred an additional 3 h at RT. Thereaction mixture was then concentrated under vacuum to a volume of 800mL keeping the flask temperature at ≦40°. The slurry was diluted with H₂O (6 L) and cooled to 5°.

The solid was removed by filtration and washed with H₂ O (2×1.5 L).* Thesolid was then suspended in a mixture of SD3A (US Industrial ChemicalsCo., a Division of National Distillers and Chemical Corp., 99 Park Ave.,New York, NY, 10016, 2.5 L) and methanesulfonic acid (Morton Thiokol,Inc.-Alfa Products, PO Box 299, 152 Andover Street, Danvers, MA, 01923,107.2 g, 1.12 mol). The resulting solution was filtered and diluted with5 L of PhCH₃. After crystallization overnight at RT, the mixture wascooled at 5° for 1 h and filtered. The solid was washed with PhCH₃ (500mL) and dried to give 417 g (93%) (after a second crop obtained from thefiltrate was added) of2-((6-chrysenylmethyl)amino)-2-methyl-1,3-propanediol methanesulfonatemp 239°-240° (dec), (C, H, N, S).

1D. 2-((6-Chrysenylmethyl)amino)-2-methyl-1,3-propanediol

To a rapidly stirred solution of2-((6-chrysenylmethyl)amino)-2-methyl-1,3-propanediol hydrochloride (1B,20 g, 52.36 mmol) in a mixture of CH₃ OH (200 mL) and H₂ O (800 mL) wasadded dropwise over 10 min a 1N NaOH solution (55 mL). The resultingwhite precipitate was filtered and washed with warm H₂ O (4×500 mL) andthen with Et₂ O (1 L), sucked dry and placed in a vacuum oven overnight.A total of 17.43 g (96.4%) of2-((6-chrysenylmethyl)amino)-2-methyl-1,3-propanediol mp 200°-202°, (C,H, N) was obtained.

1E. 2-((6-Chrysenylmethyl)amino)-2-methyl-1,3-propanediol lactate

A mixture of 2-((6-chrysenylmethyl)amino)-2-methyl-1,3-propanediol freebase (ID) (3.45 g, 10 mmol) and lactic acid (Fisher Scientific Co., 711Forbes Ave., Pittsburgh, PA, 15219, 85% liquid, 1.04 g, 10 mmol) in CH₃ON (500 mL) was brought to reflux and filtered through a glass frittedfunnel. The solvent was removed by rotary evaporation to give a crudewhite solid. This was crystallized (CH₃ OH/Et₂ O) 3× to give 1.84 g(42.2%) of 2-((6-chrysenylmethyl)amino)-2-methyl-1,3-propanediol lactatemp 163°-164°, (C, H, N).

1F. 2-((6-Chrysenylmethyl)amino)-2-methyl-1,3-propanediol.3/4citrate

A mixture of 2-((6-chrysenylmethyl)amino)-2-methyl-1,3-propanediol freebase (1D, 3.45 g, 10 mmol) and citric acid (Sigma Chemical Co., P.O. Box14508, St. Louis, MO, 63178, 1.92 g, 10 mmol) in CH₃ OH (500 mL) waswarmed until it dissolved then filtered through a glass fritted funnel.The solvent was then removed to give a crude white solid. This wasboiled with abs. EtOH (2×300 mL) and filtered to give a white solid.This was then recrystallized 2× (CH₃ OH/Et₂ O) filtered and driedovernight in a vacuum oven to give 1.24 g of2-((6-chrysenylmethyl)amino)-2-methyl-1,3-propanediol.3/4citrate mp146°-151°, (C, H, N).

1G.2-((6-Chrysenylmethyl)amino)-2-mthyl-1,3-propanediol-2-hydroxyethanesulfonate

2-((6-chrysenylmethyl)amino)-2-methyl-1,3-propanediol methanesulfonate(1C, 10.0 g, 26.63 mmol) was neutralized with 1N NaOH (30 mL) in CH₃OH/H₂ O (200/800 mL) as in procedure 1D. The white solid which formedwas filtered, washed successively with warm H₂ O (3×500 mL), CH₃ OH (200mL), and abs. Et₂ O (2×500 mL), sucked semi-dry and then resuspended inCH₃ OH (500 mL). To this was added a 0.43M aqueous solution of2-hydroxyethanesulfonic acid (30 mL). Slight warming gave a solutionwhich was then filtered. The solvent was removed by rotary evaporationto give a wet white solid. This was triturated with dry Et₂ O, filtered,and recrystallized 3× from EtOH/Et₂ O to give 8.8 g (70.4%) of2-((6-chrysenylmethyl)amino)-2-methyl-1,3-propanediol2-hydroxyethanesulfonate, mp 212°-213°, (C, H, N, S).

EXAMPLE 2 2-((6-Chrysenylmethyl)amino)-2-hydroxymethyl-1,3-propanediolhydrochloride

Using the reductive amination procedure described in 1B,6-chrysenecarbaldehyde (1A) and tris(hydroxymethyl)aminomethane(Aldrich) gave2-((6-chrysenylmethyl)amino)-2-hydroxymethyl-1,3-propanediolhydrochloride, mp 238°-239° (dec), (CH₃ OH/Et₂ O), (C, H, Cl, N).

EXAMPLE 3 2-((6-Chrysenylmethyl)amino)-2-ethyl-1,3-propanediolhydrochloride

Using the reductive amination procedure described in 1B,6-chrysenecarbaldehyde (1A) and 2-amino-2-ethyl-1,3-propanediol(Aldrich) gave 2-((6-chrysenylmethyl)amino)-2-ethyl-1,3-propanediolhydrochloride, mp 241°-243° (dec), (EtOH/Et₂ O), (C, H, Cl, N).

EXAMPLE 42-(((12-Chloro-6-chrysenyl)methyl)amino)-2-methyl-1,3-propanediol 4A.12-Chloro-6-chrysenecarbaldehyde

6-Chlorochrysene (Cambridge Chemical, Inc., 70 g, 0.266 mol) wasformylated according to the procedure outlined in 1A, except that CH₂Cl₂ (2.5 L) was used as the reaction solvent. Chromatography on a plugof SiO₂ (1 kg) using EtOAc as the eluting solvent afforded after removalof solvent and drying 19.1 g (25%) of 12-chloro-6-chrysenecarbaldehydemp 255°-257°, (EtOAc).

4B. 2-(((12-Chloro-6-chrysenyl)methyl)amino)-2-methyl-1,3-propanediolmethanesulfonate.1/3H₂ O

Using the reductive amination procedure outlined in 1C,12-chloro-6-chrysenecarbaldehyde (4A) and2-amino-2-methyl-1,3-propanediol (Aldrich) gave2-(((12-chloro-6-chrysenyl)methyl)amino)-2-methyl-1,3-propanediolmethanesulfonate.1/3H₂ O mp 233°-233.5° (dec), (EtOH/Et₂ O), (C, H, Cl,N, S).

EXAMPLE 5(+-)-(2R*,3RS*,4R*)-3-((6-Chrysenylmethyl)amino)-3-methyl-2,5-pentanediol5A. 3-Methyl-3-nitro-2,4-pentanediols

Solid NaOH (Mallinckrodt, 286 mg, 7.15 mmol) was added to a solution of3-nitro-2-butanol (Aldrich, 59.6 g, 0.50 mol) and acetaldehyde (Eastman132 g, 1.50 mol) in anhydrous DMSO (MCB, 100 mL). The reaction wasstirred under N₂ for 5 days. Glacial acetic acid (0.5 mL) was then addedto the solution. The solvent was then removed by rotary evaporation,(45° C. bath temperature) to give a yellow liquid. This was diluted withH₂ O (200 mL) and extracted with CH₂ Cl₂ (5×200 mL). The combined CH₂CL₂ extracts were washed sequentially with H₂ O (50 mL) and satd. NaCl(50 mL), dried (MgSO₄) and filtered. Volatile components were removedfrom the filtrate under vacuum (first at aspirator vacuum then at 0.1 mm(bath temperature of 50°-135°)) leaving a viscous yellow liquid (53.0 g,64%). This was mixed with EtOAc/hexane (1:1) (50 mL) and subjected toflash chromatography on SiO₂ (1.5 kg), using 11 L of EtOAc/hexane (1:1)as the eluting solvent and collecting 500 mL fractions. Appropriatefractions were combined and the solvent removed by rotary evaporation togive a total of 43.5 g (53%) of the diastereomeric mixture of3-methyl-3-nitro-2,4-pentanediols (two meso forms and a dl pair, easilydistinguished by NMR in DMSO-d₆).

5B. meso-3-Nitro-3-methyl-2,4-pentanediol and 5C.(+-)(2R*,3RS,4R*)-3-Nitro-3-methyl-2,4-pentanediol

The chromatographic process described above gave partial separation ofthe diastereomers. The early fraction (500 mL) gave 13.1 g one of themeso-3-nitro-3-methyl-2,4-pentanediols (5B) as a colorless solid mp60°-61° (C, H, N). The remaining fractions were combined to give 38.3 gof the isomeric mixture containing both the meso- and dl-compounds.Recrystallization from EtOAc/hexane (300 mL, 2:1) gave 27.8 g of a 4:1ratio of (+-)(2R*,3RS,4R*)-3-nitro-3-methyl-2,4-pentanediol (5C) and theother of the meso-3-nitro-3-methyl-2,4-pentanediols mp 79°-86° (C, H,N). These two materials were then used without further purification.

5D. (+-)-(2R*,3RS,4R*)-3-Amino-3-methyl-2,4-pentanediol acetate

To a solution of 3-methyl-3-nitro-2,4-pentanediols (5C, 16.3 g, 0.1 mol;the 4:1 mixture of dl pair to one meso form described above) in 95% EtOH(150 mL) was added glacial acetic acid (19 mL) and 10% Pd/C (MCB, 2.0g). The reduction was carried out in a Parr apparatus at 50 psi of H₂during a 70 h period of RT. The catalyst was removed by filtrationthrough a Millipore® filter and the solvent removed under vacuum (RT, 2days). The viscous, colorless syrup was dissolved in abs. EtOH (30 mL).While slightly warm, the solution was made cloudy by adding anhydrousEt₂ O (100 mL) and was then placed in a refrigerator. Colorless crystalsformed over two days which were filtered, washed with Et₂ O and dried ina vacuum oven (at RT). The yield of pure(+-)-(2R*,3RS,4R*)-3-amino-3-methyl-2,4-pentanediol acetate (as shown byNMR in DMSO-d₆) was 12.8 g mp 110.5°-112° (C, H, N). USSR patent No.521,272 (CA 85: 177498) mentions 3-amino-3-methyl-2,4-pentanediol as anintermediate but no synthetic details, physical properties, orstereochemistry was presented in the abstract.

5E. meso-3-Amino-3-methyl-2,4-pentanediol acetate

Using the procedure described in 5D,meso-3-methyl-3-nitro-2,4-pentanediol (5B, undetermined configuration)gave meso-3-amino-3-methyl-2,4-pentanediol acetate (53%), mp 137°-138°,(C, H, N).

5F. (+-)(2R*,3RS,4R*)3-(6-Chrysenylmethylamino)-3-methyl-2,5-pentanediolmethanesulfonate

To a RB flask was added(+-)(2R*,3RS,4R*)-3-amino-3-methyl-2,4-pentanediol acetate (5D) and anequimolar amount of NaOCH₃ (MCB) and CH₃ OH (100 mL). After briefwarming to aid solution, the solvent was removed by rotary evaporationand after addition of chrysene-6-carbaldehyde (1A), the reaction runfollowing the normal reductive amination procedure outlined in 1C togive(+-)(2R*,3RS,4R*)3-((6-chrysenylmethylamino)-3-methyl-2,5-pentanediolmethanesulfonate mp 182°-183° (dec), (EtOH/Et₂ O), (C, H, N, S).

EXAMPLE 6(+-)(2R*,3S*)-2-((6-Chrysenylmethyl)amino)-2-methyl-1,3-butanediol 6A.(+-)(2R*,3S*)-2-Methyl-2-nitro-1,3-butanediol and 6B.(+-)(2R*,3R*)-2-Methyl-2-nitro-1,3-butanediol

To a mixture of 2-nitro-1-propanol (Aldrich, 63.0 g, 0.60 mol) andacetaldehyde (Eastman, 39.6 g, 0.90 mol) cooled in an ice bath under N₂was added cold H₂ O (40 mL) and calcium hydroxide (200 mg). The mixturewas allowed to warm to RT over 2 h and then stirred for 68 h. Theresulting solution was neutralized with excess solid CO₂. The mixturewas stirred for 1 h before filtration through a Millipore® filter. Thefiltrate was the concentrated under vacuum at 35°. The residue, aviscous syrup partially crystallized on drying under vacuum (0.1 mm, RT,48 h) was then triturated with cold Et₂ O (35 mL). Solid white crystalswhich formed were collected by filtration, washed with cold Et₂ O (3×15mL) and dried under vacuum (0.1 mm, RT) to give 34.1 g of material,judged by NMR to be (+-)(2R*,3S*)-2-methyl-2 -nitro-1,3-butanediol (6A)(purity >97%, racemic). After recrystallization, the diastereomericpurity was >99%, mp 78.5°-81° (lit. 78°; cf. Beil 1, 482, in Henry,Bull. Soc. Chim. Fr. [3] 15, 1224), (C, H, N).

The original filtrate (including washes) was concentrated under vacuumto a pale yellow liquid which was subjected to flash chromatography asfollows: The sample was mixed with hexane/EtOAc (2:1, 100 mL) and addedto a column of dry SiO₂ (1.5 kg). The column was eluted withhexane/EtOAc (2:1, 12 L) then hexane/EtOAc (1:1, 6 L) while 500 mLfractions were collected. Appropriate fractions were combined. Pureproduct was found in the final 8 L; yield, 38.7 g viscous syrup, judgedby NMR to be a 1:1 mixture of the two racemic diastereomers (6A and 6B),(C,H,N).

This and another batch of the 1:1 diasteriomeric mixture of 6A and 6B(prepared as described above) were combined (67 g, total) and subjectedto successive liquid-liquid partitioning between H₂ O and EtOAc to givepure samples (99% on the basis of NMR and HPLC (Hamilton PRP-1 columnusing 3.5% aqueous acetonitrile as the mobile phase)) of(+-)(2R*,3S*)-2methyl-2-nitro-1,3-butanediol (6A) (24.9 g, k'=4.3, mp79°-81°, C,H,N) and (+-)(2R*,3R*)-2-methyl-2-nitro-1,3-butanediol (6B)(15.8 g, k'=2.1, C,H,N, a colorless, viscous liquid).

6C. (+-)(2R*,4S*,5R*)-4,5-dimethyl-5-nitro-2-pheny-1,3-dioxane and 6D.(+-)(2R*,4S*,5S*)-4,5-dimethyl-5-nitro-2-phenyl-1,3-dioxane

The relative configurations of the two diasteriomeric pairs (6A and 6B)were inequivocably assigned on the basis of comparative NMR analysis ofthe respective cyclic acetals derived from benzaldehyde. Thus, 6A (1.49g, 0.01 mol) and benzaldehyde (Mallinckrodt, 1.06 g, 0.01 mol) werecondensed in benzene in the presence of a catalytic amount ofp-toluenesulfonic acid (Fisher) with azeotropic removal of water(according to the method of H. Piotrowska, B. Serafin and T. Urbanski,Tetrahedron 109, 379 (1963)). After successive washing with satd. NaHCO₃solution, drying (MgSO₄), filtration, and removal of the benzene byrotary evaporation, a pale yellow solid was obtained. A solution of thisproduct in ethanol at 0° C. provided an oil which was isolated bydecanting the mother liquor and drying under vacuum (0.1 mm, RT). Theyield was 1.48 g (62%) of(+-)(2R*,4S*,5R*)-4,5-dimethyl-5-nitro-2-phenyl-1,3-dioxane (6C)(C,H,N).

Similarly prepared from 6B and benzaldehyde was(+-)(2R*,4S*,5S*)-4,5-dimethyl-5-nitro-2-phenyl-1,3-dioxane (6D) (74%)(C,H,N).

6E. (+-)(2R*,3R*)-2-Amino-2-methyl-1,3-butanediol acetate

Using the procedure described for 5D,(+-)(2R*,3R*)-2-methyl-2-nitro-1,3-butanediol (6B) gave(+-)(2R*,3R*)-2-amino-2-methyl-1,3-butanediol acetate (97%) mp 117°-121°(C,H,N).

6F. (+-)(2R*,3S*)-2-Amino-2-methyl-1,3-butanediol acetate

Using the procedure described for 5D(+-)(2R*,3S*)-2-methyl-2-nitro-1,3-butanediol (6A) gave(+-)(2R*,3S*)-2-amino-2-methyl-1,3-butanediol acetate (93%) mp 163°-165°(C,H,N).

6G. (+-)(2R*,3S*)-2-(6-Chrysenylmethylamino)-2-methyl-1,3-butanediolhydrochloride.1/3 H₂ O

To a RB flask was added (+-)(2R*,3S*)-2-amino-2-methyl-1,3-butanediolacetate (6F) and an equimolar amount of sodium methoxide (MCB) and CH₃OH (100 mL). After warming, the solvent was removed by rotaryevaporation, and after addition of chrysene-6-carbaldehyde (1A) thereaction run following the normal reductive amination procedure outlinedin 1B to give(+-)(2R*,3S*)-2-((6-chrysenylmethyl)amino)-2-methyl-1,3-butanediolhydrochloride.1/3 H₂ O mp 238°-239° (dec), (EtOH/Et₂ O), (C,H,Cl,N).

6H. (+-)(2R*,3S*)-2-((6-Chrysenylmethyl)amino)-2-methyl-1,3-butanediolmethanesulfonate

Using the reductive amination procedure outlined in 1C, the twointermediates in 6G gave(+-)(2R*,3S*)-2-((6-chryenylmethyl)amino)-2-methyl-1,3-butanediolmethanesulfonate mp 220°-221° (dec), (EtOH/Et₂ O), (C,H,N,S).

EXAMPLE 7(+-)-(2R*,3R*)-2-((6-Chrysenylmethyl)amino)-2-methyl-1,3-butanediolhydrochloride

Using the procedure outlined for 6G, chrysene-6-carbaldehyde (1A) and(+-)(2R*,3R*)-2-amino-2-methyl-1,3-butanediol acetate (6E) gave(+-)(2R*,3R*)-2-((6-chrysenylmethyl)amino)-2-methyl-1,3-butanediolhydrochloride mp 236°-237.5° (dec), (CH₃ OH/Et₂ O), (C,H,Cl,N).

EXAMPLE 8 2-((6-Chrysenylmethyl)amino)-2-ethoxymethyl-1,3-propanediol8A. 3,5-Diphenyl-7a(7H)-ethoxymethyl-1H,3H,5H-oxazolo(3,4-c)oxazole

A mechanically stirred 60% dispersion of NaH in mineral oil (Alfa, 34.0g, 0.85 mol) was washed with dry hexane to remove the oil and suspendedin dry DMF (300 ml). To the mixture was added a solution of3,5-diphenyl-1H,3H,5H-oxazolo(3,4-c)oxazole-7a(7H)-methanol (208.2 g,0.7 mol, prepared by the method of J. Pierce et al., J. Amer. Chem. Soc.73 2595 (1951) in dry DMF (300 mL) keeping the reaction mixture between30°-35°. The salt suspension was stirred at RT for 60 min, diluted withdry DMF (200 mL) to facilitate stirring, cooled, then treated with ethyliodide (Aldrich, excess) at such a rate that the reaction temperaturewas between 20°-35°. The mixture was stirred at RT for 2 h, thencautiously treated with abs. EtOH (30 mL). The resulting mixture wasdiluted with Et₂ O (2.5 L) and the resulting solids removed byfiltration. The solvent was then removed using a rotary evaporator togive 229.5 g of a yellow oil containing both starting material anddesired product. A solution of the oil in chloroform was mixed with SiO₂(200 g) and the solvent removed. The solid was then added to a column ofSiO₂ (800 g). Elution with the EtOAc/hexane (1:3.5) gave 139.7 g (61.3%)of 3,5-diphenyl-7a(7H)-ethoxymethyl-1H,3H,5H-oxazolo(3,4-c)oxazole. Ananalytical sample was obtained by recrystallization from hexane, mp83.5°-85°, (C,H,N). The bulk of the material was used without furtherpurification.

8B. 2-Amino-2-ethoxymethyl-1,3-propanediol hydrochloride.1/4 H₂ O

3,5-Diphenyl-7a(7H)-ethoxymethyl-1H,3H,5H-oxazolo(3,4-c)oxazole (8A, 136g, 0.42 mol) was dissolved in 6N HCl (400 mL) and the resulting solutionstirred 1.5 h at RT. After extraction with Et₂ O (2×200 mL) to removebenzaldehyde, the aqueous solution was concentrated on a rotaryevaporator to give a colorless oil. This was cooled in an ice bath tofacilitate crystallization. The solid which formed was slurried withcold CH₃ CN, filtered, then washed with Et₂ O and dried in a vacuum ovenat RT to give 71 g (89%) of 2-amino-2-ethoxymethyl-1,3-propanediolhydrochloride.1/4H₂ O mp 78°-79°, (C,H,Cl,N).

8C. 2-((6-Chrysenylmethyl)amino)-2-ethoxymethyl-1,3-propanediolhydrochloride

To a RB flask was added 2-amino-2-ethoxymethyl-1,3-propanediolhydrochloride.1/4 H₂ O (8B) and an equimolar amount of sodium methoxide(MCB) and CH₃ OH (100 mL). After warming, the solvent was removed byrotary evaporation, and after addition of chrysene-6-carbaldehyde (1A),the reaction run following the normal reductive amination procedureoutlined in 1C to give2-((6-chrysenylmethyl)amino)-2-ethoxymethyl-1,3-propanediolhydrochloride, mp 230°-232° (dec), (CH₃ OH/Et₂ O), (C,H,Cl,N).

EXAMPLE 9 3-Methoxy-2-((6-chrysenylmethyl)amino)-2-methyl-1-propanol 9A.4-Aza-3-hydroxymethyl-3-methyl-1-oxaspiro[4.5]decane

A solution of 2-amino-2-methyl-1,3-propanediol (Aldrich, 303.4 g, 3.0mol), cyclohexanone (Fisher, 294.5 g, 3.0 mol) and PhCH₃ (400 mL) wasrefluxed for approximately 2 h with azeotropic removal of H₂ O. Thematerial which crystallized from the PhCH₃ on cooling was recrystallized2× from hexane to give 444.4 g of4-aza-3-hydroxymethyl-3-methyl-1-oxaspiro[4.5]decane (80%) mp 52°-54°,(C,H,N).

9B. 4-Aza-3-methoxymethyl-3-methyl-1-oxaspiro[4.5]decane

A mechanically stirred 60% dispersion of NaH in mineral oil (Alfa, 75 g,1.9 mol) was washed with dry hexane to remove the oil and suspended indry DMF (200 mL). To the mixture was added a solution of4-aza-3-hydroxymethyl-3-methyl-1-oxaspiro[4.5]decane (9A, 27.8 g, 1.5mol) in dry DMF (200 mL) keeping the reaction mixture temperaturebetween 30°-35°. Small amounts of DMF were added as necessary tofacilitate stirring. The mixture was stirred at RT for 1.5 h, thencooled and treated with methyl iodide (Fisher, 234.2 g, 102.7 mL, 1.65mol) keeping the reaction temperature between 20°-30°. The mixture wasstirred 2 h at RT and slowly treated with abs. EtOH (40 mL), thendiluted with dry Et₂ O (3 L). The reaction mixture was filtered, and thesolvent removed by rotary evaporation. The residue was then fractionallydistilled to give 209.7 g (70.3%) of4-aza-3-methoxymethyl-3-methyl-1-oxaspiro[4.5]decane as a colorlessliquid bp 114°/14 mm, (C,H,N).

9C. 2-Amino-3-methoxy-2-methyl-1-propanol

A solution of 4-aza-3-methoxymethyl-3-methyl-1-oxaspiro[4.5]decane (9B,299 g, 1.5 mol) and 6N HCl (500 mL) was refluxed for 60 min. On cooling,two layers formed, the upper one containing cyclohexanone was removed byextraction with Et₂ O (2×400 mL). The lower aqueous layer wasconcentrated on a rotary evaporator to give a syrup which then wastreated with excess 50% NaOH. The resulting slurry was extracted withEt₂ O/CH₂ Cl₂ (2:1, 4x500 mL), then with CH₂ Cl₂ (500 mL). The solventwas removed by rotary evaporation to give 198 g of pale oil. Fractionaldistillation of this oil gave 166 g (93%) of2-amino-3-methoxymethyl-1-propanol as a colorless oil bp 94° C./17 mm,(C,H,N).

9D. 3-Methoxy-2-((6-chrysenylmethyl)amino)-2-methyl-1-propanolhydrochloride

Using the reductive amination procedure outlined in 1C,chrysene-6-carbaldehyde (1A) and 2-amino-3-methoxy-2-methyl-1-propanol(9C) gave 3-methoxy-2-((6-chrysenylmethyl)amino)-2-methyl-1-propanolhydrochloride mp 233°-234° (dec), (EtOH/Et₂ O), (C,H,Cl,N).

EXAMPLE 10 (1α,2β,3α)-2-((6-Chrysenylmethyl)amino)-1,3-cyclohexanediol10A. 1α,2β,3α-2-Amino-1,3-cyclohexanediol acetate

This compound was prepared by the method of F. Lichtenthaler (Ber. 96,845 (1963), mp 175°-177°, (C,H,N), (lit. 178°-179°, F. Lichtenthaler,(Ber. 96, 851 (1963).

10B. (1α,2β,3α)-2-((6-Chrysenylmethyl)amino)-1,3-cyclohexanediolhydrochloride

To a RB flask was added (1α,2β,3α)-2-amino-1,3-cyclohexanediol acetate(10A) and an equimolar amount of NaOCH₃ (MCB) and CH₃ OH (100 mL). Afterwarming, the solvent was removed by rotary evaporation, and afteraddition of chrysene-6-carbaldehyde (1A), the reaction run following thenormal reductive amination procedure outlined in 1C to give(1α,2β,3α)-2-((6-chrysenylmethyl)amino)-1,3-cyclohexanediolhydrochloride mp 280°-282° (dec), (CH₃ OH/Et₂ O), (C,H,Cl,N).

10C. (1α,2β,3α)-2-((6-Chrysenylmethyl)amino)-1,3-cyclohexanediolmethanesulfonate

Using the procedure in 1D, 10B was converted to its free base. Additionof an equivalent of methanesulfonic acid (Alfa, 99.5%) followed byrecrystallization (EtOH/Et₂ O) gave(1α,2β,3α)-2-((6-chrysenylmethyl)amino)-1,3-cyclohexanediolmethanesulfonate mp 280°-281° (dec), (C,H,N,S).

EXAMPLE 11 2-((6-Chrysenylmethyl)amino)-2-isopropyl-1,3-propanediol 11A.2-Isopropyl-2-nitro-1,3-propanediol

A solution of 2-methyl-1-nitropropane (38.7 g, 0.375 mol, prepared bythe procedure of N. Kornblum, B. Tunbe, and H. Ungnade, J. Amer. Chem.Soc., 76, 3209 (1954)) and NEt₃ (Eastman, 3.79 g, 0.0375 mol) in CH₃ OH(50mL) was added dropwise 37 % aqueous formaldehyde solution(Mallinckrodt, 76.2 g, 0.938 mol) at a rate such that the reactionmixture temperature did not exceed 30°. After 72 h, the solution wasconcentrated under vacuum and the residue was dissolved in H₂ O (250mL). The solution was continuously extracted for 1 h with CH₂ Cl₂ (1 L).The CH₂ Cl₂ solution was dried (MgSO₄), filtered, and concentrated togive 53.3 g (87%) of 2-isopropyl-2-nitro-1,3-propanediol, as a waxy,white solid mp 67°-72° C. (lit. mp 87°-88° B. M. Vanderbilt and H. B.Hass, Ind. Eng. Chem. 32, 34 (1940). In our hands this procedure failedto give the desired compound).

11B. 2-Amino-2-isopropyl-1,3-propanediol acetate

Using the procedure in 5D, 2-isopropyl-2-nitro-1,3-propanediol (11A)gave a 98% yield of 2-amino-2-isopropyl-1,3-propanediol acetate mp155°-155.5°. H. S. Broadbent et al., J. Heterocyclic Chem., 13, 337(1975) report the synthesis of this compound as the free base (mp70°-72° )).

11C. 2-((6-Chrysenylmethyl)amino)-2-isopropyl-1,3-propanediolhydrochloride 1/3 H₂ O

To a RB flask was added 2-amino-2-isopropyl-1,3-propanediol acetate.1/4H₂ O (11B) and an equimolar amount of sodium methoxide (MCB) and CH₃ OH(100 mL). After warming, the solvent was removed by rotary evaporationand after addition of chrysene-6-carbaldehyde (1A), the reaction runfollowing the normal reductive amination procedure outlined in 1B togive 2-((6-chrysenylmethyl)amino)-2-isopropyl-1,3-propanediolhydrochloride. H₂ O mp 223°-223.5° (dec), (EtOH/Et₂ O), (C,H,Cl,N).

EXAMPLE 12 2-((6-Chrysenylmethyl)amino)-2-methyl-1,4-butanediol 12A.Ethyl N-benzylidene-l-alaninate

Ethyl N-benzylidene-l-alaninate was prepared according to the generalprocedure of G. Stork et al., J. Org. Chem. 41 349 (1976), bp 98°-100°0.4 mm (lit. 100°/0.3 mm, A Calcagni et al., Synthesis 445 (1981)).

12B. 2-(2-Iodoethoxy)tetrahydro-2-H-pyran

Freshly distilled dihydropyran (Aldrich, 59.0 g, 0.7 mol) was addeddropwise to a cooled solution of 2-iodoethanol (Aldrich, 98 g, 0.57 mol)in Et₂ O (1 L) containing 0.1 g of p-toluenesulfonic acid (Eastman). Thesolution was then stirred for 1 h at 5°. Solid K₂ CO₃ (Mallinckrodt, 5g) was then added to the reaction mixture and the resulting suspensionstirred an additional 1 h at RT. The reaction was then filtered and theremaining solid washed with Et₂ O (1 L). The organic solutions werecombined and concentrated rotary evaporation (in a flask washed with 1%NEt₃ in H₂ O). The crude 2-(2-iodoethoxy)tetrahydro-2-H-pyran (˜100 g,68.9%) was used without further purification.

12C. Ethyl2-benzylideneamino-2-methyl-4-((tetrahydro-2H-pyran-2-yl)oxy)butyrate

A solution of lithium diisopropylamide was prepared by dropwise additionof n-BuLi (Aldrich 1.6 M in hexane, 228 mL, 0.365 mol) to a solution ofdiisopropylamine (Aldrich, 51.6 g, 0.51 mol) in a mixture of dry THF(700 mL) and dry HMPA (Aldrich, 40 mL) kept at 30°-40°. The solution wasthen cooled to -70° and a solution of ethyl N-benzylidene--l-alaninate(12A, 74.9 g, 0.365 mol) was added dropwise to the solution allowing thereaction mixture warm to -20° for several min. The resulting redsolution ws then cooled to -70°. 2-(2-Iodoethoxy)tetrahydro-2-H-pyran(12B, 98.1 g, 0.383 mol) was then added to the solution at such a ratethat the temperature in the reaction mixture did not rise above -65°.The solution was allowed to warm slowly to RT and stirred for 14 h. Thevolume of the solution was reduced to ˜300 mL by a stream of dry N₂during the last few hours to facilitate the final workup. The reactionwas quenched with satd. NaCl (800 mL) and diluted with Et₂ O (800 mL).The Et₂ O was removed and the aqueous layer extracted with hexane (500mL). The Et₂ O and hexane layers were combined and dried (Na₂ SO₄). Thesolution was filtered and the solvent removed to give 124 g of crude redoil. Bulb to bulb distillation (in 1% aq. NEt₃ washed glassware) (210°bath temperature/0.3 mm) gave 95 g of ethyl2-benzylideneamino-2-methyl-4-((tetrahydro-2H-pyran-2-yl)oxy)butyratewhich was homogeneous by vpc and gave acceptable NMR and mass spectra.It was stored under N₂ in the refrigerator and was used without furtherpurification.

12D. 2-Benzylamino-2-methyl-4-((tetrahydro-2H-pyran-2-yl)oxy)butanol

A solution of ethyl2-benzylideneamino-2-methyl-4-((tetrahydro-2H-pyran-2-yl)oxy)butyrate(12C, 100.0 g, 0.3 mol) in THF (100 mL) was added slowly to a suspensionof lithium aluminum hydride (Alfa, 22.77 g, 0.6 mol) rapidly stirred indry THF (1 L) at such a rate to maintain a gentle reflux. After theaddition was complete the mixture was refluxed for 4 h. The reactionmixture was cooled and treated successively with H₂ O (23 mL), 15N NaOH(23 mL) and H₂ O (45 mL). The solid was removed by filtration and washedwith THF (200 mL). The organic layers were combined and concentrated byrotary evaporation to give2-benzylamino-2-methyl-4-((tetrahydro-2H-pyran-2-yl)oxy)butanol (81.1 g,92.0%) as a thick oil which was used without further purification.

12E. 2-Benzylamino-2-methyl-1,4-butanediol

The crude2-benzylamino-2-methyl-4-((tetrahydro-2H-pyran-2-yl)oxy)butanol (12D,80.1 g, 0.273 mol) was dissolved in 3N NCl (128 mL). After 5 min themixture was washed with Et₂ O (200 mL). The aqueous solution wasconcentrated by rotary evaporation to give a thick oil which was cooledand basified with excess 50% NaOH. The oily amine which formed wasextracted with Et₂ O (3×200 mL). The Et₂ O extracts were combined andconcentrated to give 63.6 g of a thick oil. Distillation gave 49.8 g(94%) of 2-benzylamino-2-methyl-1,4-butanediol as a pale yellow oil (bp168°-170°/0.35 mm) (C,H,N).

12F. 2-Amino-2-methyl-1,4-butanediol hydrochloride2-Benzylamino-2-methyl-1,4-butanediol (12E, 31.08 g, 0.149 mol) wasdissolved in 95% EtOH (240 mL) containing conc. HCl (21 mL, 0.25 mol)and 5% Pd/C (10.0 g) and reduced in a Parr apparatus at 40 psi over 37 hat RT. The catalyst was then removed by filtration and the solventremoved by rotary evaporation (bath at 60°) to give 20.91 g of2-amino-2-methyl-1,4-butanediol hydrochloride (90.2%) as a clear, thick,colorless oil with acceptable NMR and mass spectra. It was used withoutfurther purification. This compound has been reported as its acetatesalt (G. Cardillo et al., Chem. Commun. 1308, 1982), but no data wasgiven. Attempts to duplicate the latter procedure were unsuccessful.12G. 2-((6-Chrysenylmethyl)amino)-2-methyl-1,4-butanediolhydrochloride.1/3 EtOH

To a RB flask was added 2-amino-2methyl-1,4-butanediol hydrochloride(12F) and an equal amount of sodium methoxide (MCB) and enough CH₃ OH toform a solution when warmed. The solvent was then removed by rotaryevaporation and after addition of chrysene-6-carbaldehyde (1A), thereaction run following the normal reductive amination procedure outlinedin 1C to give 2-((6-chrysenylmethyl)amino)-2-methyl-1,4-butanediolhydrochloride.1/3 EtOH mp 233°-235° (dec), (EtOH/Et₂ O), (C,H,Cl,N).

EXAMPLE 13 meso-3-((6-Chrysenylmethyl)amino)-2,4-pentanediol 13A.3-Nitro-2,4-pentanediol

A solution of nitromethane (Aldrich, 73.3 g, 1.2 mol) and acetaldehyde(Eastman, 158.6 g, 3.6 mol) was cooled in a ice bath. H₂ O (80 mL) andCa(OH)₂ (0.40 g) were then added to the flask. The mixture was stirredunder N₂ for 8 h, neutralized with CO_(a) and filtered. The filtrate wasextracted continuously with CH₂ Cl₂ (1 L) for 6 h. The CH₂ Cl₂ extractwas concentrated under vacuum to give 114.6 g (77%) of crude3-nitro-2,4-pentanediols as, a pale yellow syrup. This material wasunstable and was used without further purification. Z. Eckstein and T.Urbanski, Roczniki Chem. 26,571 (1952), also report the synthesis andisolation as a crude material of this material.

13B. (2α,4α,5α,6α)-4,6-Dimethyl-5-nitro-2-phenyl-1,3-dioxane

A solution of the crude mixture of 3-nitro-2,4-pentanediols (13A, 115 g,˜0.77 mol) from above, benzaldehyde (Fisher 81.7 g, 0.77 mol) andp-toluenesulfonic acid (Fisher, 1.28 g) in benzene (400 mL) was refluxedfor 1.5 h with azeotropic removal of H₂ O. After removal of the solventunder vacuum, the crude product (a complex mixture) was dissolved inabs. EtOH (150 mL). After 36 h, the crystals that had formed (RT) werecollected and dried to give yield 25.8 g, of a 5:1 mixture (based inNMR) of desired product and another isomer (C,H,N). Pure2α,4α,5α,6α-4,6-dimethyl-5-nitro-2-phenyl-1,3-dioxane was obtained afterrecrystallization from abs. EtOH mp 117.5°-118° (C,H,N).

13C. meso-3-Amino-2,4-pentanediol acetate

(2α,4α,5α,6α)-4,6-Dimethyl-5-nitro-2-phenyl-1,3-dioxane was reduced asdescribed in 5D except that the temperature was 50° C. Recrystallization(95% EtOH) gave meso-3-amino-2,4-pentanediol acetate mp 108.5°-109.5°,(C,H,N).

13D. meso-3-((6-Chrysenylmethyl)amino)-2,4-pentanediol methanesulfonate

To a RB flask was added meso-3-amino-3-methyl-2,4-pentanediol acetate(13C) and an equimolar amount of NaOCH₃ (MCB) and CH₃ OH (100 mL). Afterwarming to aid solution the solvent was removed by rotary evaporation.After addition of chrysene-6-carbaldehyde (1A), the reaction was runfollowing the normal reductive amination procedure outlined in 1C togive meso-3-((6-chrysenylmethyl)amino)-2,4-pentanediol methanesulfonatemp 221-223), (CH₃ OH/Et₂ O), (C,H,N,S).

EXAMPLE 14 2-((6-Chrysenylmethyl)amino)-1,3-propanediol methanesulfonate

Using the reductive amination procedure outlined in 1C,chrysene-6-carbaldehyde (1A) and 2-amino-1,3-propanediol hydrochloride(Simga) gave 2-((6-chrysenylmethyl)amino)-1,3-propanediolmethanesulfonate mp 208°-209°, (CH₃ OH/Et₂ O), (C,H,N,S).

EXAMPLE 152-(((12-Ethyl-6-chrysenyl)methyl)amino)-2-methyl-1,3-propanediol 15A.12-Ethyl-6-chrysenecarbaldehyde

6-Ethylchrysene (Cambridge Chemical, Inc., 60 g, 0.234 mol) wasformylated according to the procedure outlined in 1A, except that CH₂Cl₂ ( 1 L) was used as the reaction solvent. The crude material waschromatographed on a plug of SiO₂ (1 kg) using PhCH₃ as the elutingsolvent, afforded 50.38 g (76%) of 12-ethyl-6-chrysenecarbaldehyde mp138°-139°, (C,H).

15B. 2-(((12-Ethyl-6-chrysenyl)methyl)amino)-2-methyl-1,3-propanediolmethanesulfonate

Using the reductive amination procedure outlined in 1C,12-ethyl-6-chrysenecarbaldehyde (15A) and2-amino-2-methyl-1,3-propanediol (Aldrich) gave2-(((12-ethyl-6-chrysenyl)methyl)amino)-2-methyl-1,3-propanediolmethanesulfonate mp 189°-192° (dec), (EtOH/Et₂ O), (C,H,N,S).

EXAMPLE 16 2-((6-Chrysenylmethyl)amino)-2-methyl-1,3-propanedioldiacetate

A mixture of 2-((6-chrysenylmethyl)amino)-2-methyl-1,3-propanediolhydrochloride (1B, 5.0 g, 13.1 mmol) and acetylchloride (Aldrich, 5.0mL, 70.3 mmol) was refluxed in dry THF (200 mL) under N₂ for 12 h. Thereaction mixture was poured into a satd. NaHCO₃ solution (500 mL) andextracted with EtOAc (3×500 mL). The EtOAc layers were combined, dried(K₂ CO₃) and filtered to give a slightly yellow liquid. The solvent wasremoved to give an off-white solid. This was recrystallized 3× fromPhCH₃ /hexane (1:1). After filtration and drying, 3.67 g (65.2%) of2-((6-chrysenylmethyl)amino)-2-methyl-1,3-propanediol diacetate wasobtained mp 136°-137.5°, (C,H,N).

EXAMPLE 172-(((12-Ethoxy-6-chrysenyl)methyl)amino)-2-methyl-1,3-propanediolmethanesulfonate 17A. 12-Ethoxychrysene-6-carbaldehyde

6-Erthoxychrysene (Cambridge Chemical, Inc., 48 g, 0.176 mol) wasformylated according to the procedure outlined in 1A, except that CH₂Cl₂ (1 L) was used as the reaction solvent. After isolation, the crudematerial was chromatographed on a plug of SiO₂ (500 g) using CH₂ Cl₂ asthe eluting solvent to give (after removal of solvent and drying) 33.7 g(64%) of 12-ethoxychrysene-6-carbaldehyde mp 173.5°-176°, (C,H).

17B. 2-(((12-Ethoxy-6-chrysenyl)methyl)amino)-2-methyl-1,3-propanediolmethanesulfonate

Using the reductive amination procedure described in 1C,12-ethoxy-6-chrysenecarbaldehyde (17A) and2-amino-2-methyl-1,3-propanediol (Aldrich) gave2-(((12-ethoxy-6-chrysenyl)methyl)amino)-2-methyl-1,3-propanediolmethanesulfonate mp 202°-204° (dec) (EtOH/Et₂ O), (C,H,N,S).

EXAMPLE 18 2-((6-Chrysenylmethyl)amino)-2-methylpropanol hydrochloride

Using the reductive amination procedure described in 1C,6-chrysenecarbaldehyde (1A) and 2-methyl-2-aminopropanol (Aldrich) gave2-((6-chrysenylmethyl)amino)-2-methyl-1-propanol hydrochloride mp275°-277° (dec), (CH₃ OH/Et₂ O), (C,H,Cl,N).

EXAMPLE 19 2-((3-Chrysenylmethyl)amino)-2-methyl-1,3-propanediol 19A.2-Acetylchrysene 19B. 3-Acetylchrysene 19C. 6-Acetylchrysene

Friedel-Crafts reaction of chrysene with AlCl₃ /Ch₃ COCl/PhNO₂ gave amixture of 2-,3-, and 6-acetylchrysenes (285 g, Cambridge Chemical,Inc.). This was stirred and heated in CH₂ Cl₂ (400 mL) and thenfiltered. The insoluble material, 2-acetylchrysene, was washed copiouslywith CH₂ Cl₂. The solvent was removed from the filtrate. The resultingsolid was dissolved in PhCH₃, then the mixture containing the remainingtwo isomers chromatographed using PhCH₃ as eluting solvent on a plug ofSiO₂ (1 kg). The faster eluting isomer is 6-acetylchrysene while theslower is 3-acetylchrysene. The chromatography gave 132 g of impure6-acetylchrysene, and 76 g of impure 3-acetylchrysene. These materialswere used without further purification. Pure samples of the compoundswere obtained by preparative HPLC using PhCH₃ as the eluting solvent.

19A. 2-Acetylchrysene mp 254°-255°, (lit. mp 252°-253°, W. Carruthers,J. Chem. Soc. 3486 (1953)) (PhCH₃), (C,H), (Rf=0.50, SiO₂, PhCH₃);

19B. 3-Acetylchrysene mp 160°-161°, (lit. mp 159°, W. Carruthers, J.Chem Soc. 3486 (1953)) (CH₂ Cl₂ /MeOH), (C,H), (Rf=0.51, SiO₂, PhCH₃);

19C. 6-Acetylchrysene mp 141°-142° (lit. mp 141°, W. Carruthers, J.Chem. Soc. 3486 (1953)), (CH₂ Cl₂ /MeOH), (C,H), (Rf=0.59, SiO₂, PhCH₃).

19D. Chrysene-3-carboxylic acid

3-Acetylchrysene (19B) was converted by the method of J. van de Kamp, J.Amer. Chem. Soc. 52, 3704 (1930) to chrysene-3-carboxylic acid mp302°-304° (dec), (lit. mp 295° (dec), W. Carruthers, J. Chem. Soc. 3486(1953)), (THF/EtOH), (C,H).

19E. Ethyl chrysene-3-carboxylate

By the procedure of P. Arjunan and K. D. Berlin, Org. Prep. andProcedures 13 (5), 368 (1981), chrysene-3-carboxylic acid (19D, 18.3 g,0.067 mol) was converted to ethyl chrysene-3-carboxylate 18.09 g (90%)mp 123°-124°, (PhCH₃ /hexane), (C,H).

19F. 3-Hydroxymethylchrysene

A solution of ethyl chrysene-3-carboxylate ((19E 17.7 g, 0.059 mol) in40 mL THF was treated with LiBH₄ (Morton Thiokol, Inc.-Alfa Products, POBox 299, 152 Andover St., Danvers, MA 01923, 2.7 g, 0.12 mol) in threeportions then refluxed for 3 days. The reaction mixture was poured intoice and acidified carefully to pH 1 with 1N HCl. The precipitate wasfiltered and recrystallized from THF/hexane to afford 14.98 g (98%) of3-chrysenemethanol mp 187°-189°, (C,H).

19G. Chrysene-3-carbaldehyde

3-Hydroxymethylchrysene (19F, 14.6 g, 0.057 mol) in CH₂ Cl₂ (2 L) wastreated with BaMnO₄ (Aldrich, 29 g, 0.113 mol) and refluxed for 15 h.The reaction mixture was filtered, the solvent removed, and theresulting solid eluted through a plug of SiO₂ (500 g) using PhCH₃ as theeluting solvent. The appropriate fractions were combined andconcentrated to 75 mL. Filtration and drying of the precipitate whichformed gave 12.88 g (89%) of chrysene-3-carbaldehyde mp 177°-177.5°,(C,H).

19H. 2-((3-Chrysenylmethyl)amino)-2-methyl-1,3-propanediolmethanesulfonate

Using the reductive amination procedure outlined in 1C,chrysene-3-carbaldehyde (19G) and 2-amino-2-methyl-1,3-propanediol(Aldrich) gave 2-((3-chrysenylmethyl)amino)-2-methyl-1,3-propanediolmethanesulfonate mp 180°-182° (dec), (EtOH/Et₂ O), (C,H,N,S).

EXAMPLE 20 2-((2-Chrysenylmethyl)amino)-2-methyl-1,3-propanediol 20A.Chrysene-2-carboxylic acid

Using the method of J. van de Kamp, J. Amer. Chem. Soc. 52, 3704 (1930),except that the oxidation was run at 65° using pyridine as cosolvent toimprove the solubility, 2-acetylchrysene (19A) was converted tochrysene-2-carboxylic acid mp 337°-338° (lit. mp 325°-327° (dec), J.Chem. Soc. 3486 (1953)), (THF/EtOAc).

20B. Ethyl chrysene-2-carboxylate

By the procedure of P. Arjunan and K. D. Berlin, Org. Prep. andProcedures 13 (5), 368 (1981), chrysene-2-carboxylic acid (20A, 10.4 g,0.038 mol) was converted to ethyl chrysene-2-carboxylate 10.5 g (92%) mp205°-206°, (PhCh₃ /hexane).

20C. 2-Hydroxymethylchrysene

Ethyl chrysene-2-carboxylate (20B, 10.1 g, 0.034 mol) in THF (500 mL)was treated with LiBH₄ (Alfa, 4×0.5 g, 0.092 mol) under gentle refluxfor 4 days. The reaction mixture was poured into ice and acidifiedcarefully to pH 1 with 1M HCl. The precipitate was filtered andrecrystallized from THF/hexane to afford 8.32 g (95%) of2-chrysenemethanol mp 261°-262°, (C,H).

20D. Chrysene-2-carbaldehyde

2-Hydroxymethylchrysene (20C, 8.0 g, 0.031 mol) in CH₂ Cl₂ (2.5 L) wastreated with BaMnO₄ (Aldrich, 15.9 g, 0.062 mol) and refluxed for 12 h.The reaction mixture was filtered, and concentrated to give a solid,which was then passed through a plug of SiO₂ (500 g) using PhCH₃ as theeluting solvent. The appropriate fractions were combined and the volumereduced to 75 mL to afford 6.98 g (88%) of chrysene-2-carbaldehyde mp215°-216.5°, (C,H).

20E. 2-((2-Chrysenylmethyl)amino)-2-methyl-1,3-propanediolmethanesulfonate

Using the reductive amination procedure outlined in 1C,chrysene-2-carbaldehyde (20D) and 2-amino-2-methyl-1,3-propanediol(Aldrich) gave 2-((2-chrysenylmethyl)amino)-2-methyl-1,3-propanediolmethanesulfonate, mp 225°-227° (dec), (abs. EtOH), (C,H,N,S)

Antitumor Screening Results

Methods for evaluating the antitumor activity of these compounds areessentially those used in the Tumor Panel by the DevelopmentalTherapeutics Program, Division of Cancer Treatment, National CancerInstitute, A. Goldin, et al., Methods in Cancer Research, Vol. XVI, p.165, Academic Press (1979). Some modifications, in dose level andschedule have been made to increase the testing efficiency.

EXAMPLE 21 Lymphocytic Leukemia P388/0 Test

CD2-F₁ mice, of the same sex, weighing 20±3 g, are used for this test.Control and test animals are injected intraperitoneally with asuspension of .sup.˜ 10⁶ viable P388/0 tumor cells on day 0. In eachtest, several dose levels which bracket the LD₂₀ of the compound areevaluated; each dose level group contains six animals. The testcompounds are prepared either in physiologic saline containing 0.05%Tween 80 or distilled water containing 5% dextrose and are administeredintraperitoneally on days 1, 5, and 9 relative to tumor implant. Dosesare on a mg/kg basis according to individual animals' body weights. Theday of death for each animal is recorded, the median identified for eachgroup and the ratios of median survival time for treated (T)/control (C)groups are calculated. The criterion for activity is T/C×100≧120%.Results of P388/0 testing are summarized in Table I below.

                  TABLE I                                                         ______________________________________                                        P388/0 SCREENING RESULTS                                                                           T/C × 100%                                         Compound of                                                                             Optimal Dose                                                                             (Excluding 30 Day                                        Example No.                                                                             (mg/kg)    Survivors       LD.sub.20 A                              ______________________________________                                         1B       121        +280            140                                       1C       115        +270            105                                       2        100        +240            100                                       3        100        +240            100                                       6G        65        +245             53                                      18B        88        +240             80                                      19H       110        +120            150                                      6H         60        +235             60                                       7        110        +285            100                                       9        300        +181            425                                      10B       1013       +205            (675)                                    11C       150        +220            150                                      12G        90        +270             90                                      5F        225        +255            225                                      13D       303        +200            675                                      14        196        +270            160                                      15B       250        +130            150                                      16        1012       +145            675                                      4B        180        +155            180                                      ______________________________________                                         A. Values in parenthesis are the highest nontoxic dose where the LD.sub.2     was not determined.                                                      

EXAMPLE 22 Lymphocytic Leukemia L1210 Test

The protocol for this test is identical to that for P388/0, except thatthe number of L1210 cells implanted on day 0 is ˜10⁵ /mouse. The mouseCD2-F₁ strain is used, and the criterion for activity is T/C×100≧125%.Results of L1210 testing are summarized in Table II below.

                  TABLE II                                                        ______________________________________                                        Screening Results for L1210                                                                          T/C × 100%                                       Compound of   Dose     Excluding 30 day                                       Example No.   (mg/kg)  Survivors                                              ______________________________________                                        1C            120      +252                                                   ______________________________________                                    

EXAMPLE 23 Melanotic Melanoma B16

B6C3-F₁ mice of the same sex, weighing 20±3 g, are used for this test. Asuspension of B16 cells is prepared from a non-necrotic portion of solidtumor tissue obtained from a passage mouse. One gram of tumor ishomogenized in 9 mL ice-cold Earle's salts solution and filtered through1000 mesh screen to remove debris. 0.5 mL of the resulting brei isinjected intraperitoneally into each animal. Dosing is carried out as inthe P388/0 and L1210 tests. Days of death are recorded for a 60 dayperiod and T/C ratio calculated as in the P388/0 and L1210 tests. Thecriterion for activity is T/C×100>125%. The results of B16 testing aresummarized below in Table III.

                  TABLE III                                                       ______________________________________                                        Screening Results for B16 Melanoma                                                                   T/C × 100%                                       Compound of   Dose     Excluding 60 day                                       Example No.   (mg/kg)  Survivors                                              ______________________________________                                        1C            100      +146                                                   6G            50       +160                                                   3             70       +144                                                   2             75       +144                                                   18B           70       +125                                                   ______________________________________                                    

EXAMPLE 24 Lewis Lung Carcinoma Test

This tumor arose spontaneously in the lung of a C57B1/6 mouse and ismaintained by subcutaneous passage in that strain. The solid tumor isexcised aseptically and placed sterile saline. Pieces of viable tumortissue are minced finely with scissors and forced through a 200 meshstainless steel screen to disaggregate the tumor cells into asuspension. 10⁶ Viable cells are injected intravenously into the tailvein of BD-F₁, mice of the same sex weighing 20±3 g. In each test,several dose levels which bracket the LD₂₀ for the compound areevaluated. Ten animals are included in each dose level group, and twentyanimals in the untreated control group. The test compounds are preparedand administered on days 1, 5, and 9 as in the P388/0 protocol. The dayof death for each animal is recorded, the median identified for eachgroup and the ratios of median survival time for treated (T)/control (C)groups are calculated. The criterion for activity is T/C×100≧140%. Theresults of Lewis Lung testing are summarized in Table IV.

                  TABLE IV                                                        ______________________________________                                        Screening Results for Lewis Lung                                                                     T/C × 100%                                       Compound of   Dose     Excluding 60 day                                       Example No.   (mg/kg)  Survivors                                              ______________________________________                                        1C            105      +191                                                   ______________________________________                                    

EXAMPLE 25 Colon 38 Carcinoma Test

This chemically-induced tumor arose in a C57B1/6 mouse and is maintainedas a solid tumor in that mouse strain. The subcutaneously growing solidtumor is aseptically excised from passage mice and placed in sterilesaline. The tumor is trimmed free of visible necrotic and connectivetissue, then divided into 2-3 mm cubes. A cube is implantedsubcutaneously in the ventral thoracic region with a sterile trochar onday 0. In each test several dose levels which bracket the LD₂₀ for thecompound are evaluated. Ten animals are included in each dose levelgroup and thirty animals in the untreated control group. The testcompounds are prepared either in physiologic saline containing 0.05%Tween 80 or distilled water containing 5% dextrose and are administeredintraperitoneally on days 1, 5 and 9 after tumor implant. Doses are on amg/kg basis according to individual animals' body weights. At day 20,the animals are sacrificed and the longest (L) and shortest (W)dimensions of each tumor measured with vernier calipers. Tumor weight iscalculated from the formula (L×(W)²)/2. The criterion for activity isT/C×100≦42%. The results of Colon 38 testing are summarized in Table V.

                  TABLE V                                                         ______________________________________                                        Screening Results for Colon 38                                                Compound of    Dose                                                           Example No.    (mg/kg)  T/C × 100%                                      ______________________________________                                        1C             120      36                                                    ______________________________________                                    

EXAMPLE 26 M5076 Sarcoma Test

This sarcoma arose as a solid tumor in the ovary of a C57B1/6 mouse andwas subsequently converted to the ascitic form for intraperitioneal use.The protocol for this test is identical with that for P388/0. TheB6C3-F₁ mouse strain is used and the criterion for activity isT/C×100≧125%. Results of M5076 testing are summarized in Table VI below.

                  TABLE VI                                                        ______________________________________                                        Screening Results for M5076                                                   Compound of    Dose                                                           Example No.    (mg/kg)  T/C × 100%                                      ______________________________________                                        1C             105      +168                                                  ______________________________________                                    

EXAMPLE 27 Herpes simplex 1/vero Test

Antiviral testing against Herpes simplex 1/vero was done using plaqueinhibition methods as outlined in P. Collins and D. J. Bauer, Proc. N.Y.Acad. Sci. 284, 49 (1977) and by plaque reduction methods as outlined inP. Collins and D. J. Bauer, J. Antimicrobial Chemotherapy 3, SupplementA, 73 (1977). The column heading labeled Score, Toxicity, and Zone ofInhibition refer to the plaque inhibition screen while the IC₅₀ headingto the plaque reduction screen.

                  TABLE VII                                                       ______________________________________                                        Results of Antiviral Screening Against herpes simplex 1/vero                  Compound of                 Zone of                                           Example No.                                                                             Score.sup.A                                                                            Toxicity Inhibition.sup.B                                                                        IC.sub.50.sup.B                         ______________________________________                                        1B        -3       Y        43:ST30                                           7         -4       Y                  12                                      8C        -4       Y                  10.1                                    9D        -4       Y                  5.6                                     11C       -4       Y                  3.9                                     ______________________________________                                         .sup.A Score : 0 = no inhibition, -1 = 1-25% inhibition, -2 = 26-50%          inhibition, -3 = 51-75% inhibition, -4 = 76-100% inhibition                   .sup.B ST = slight toxicity, T = toxic                                   

EXAMPLE 28 Candida albicans Test

Antifungal testing against Candida albicans (CN 1863) was done withslight modfications using a combination of broth and agar dilutionassays as outlined in Laboratory Handbook of Medical Mycology, Chapter6, pages 441-446, M. R. McGinnis, Academic Press, New York, NY, 1980

                  TABLE VIII                                                      ______________________________________                                        Results of Antifungal Testing Against Candida albicans (CN1863)                      Compound of                                                                            MIC                                                                  Example No.                                                                            (mg/L)                                                        ______________________________________                                               1B       100                                                                  3        100                                                                  6G       100                                                                  18B       30                                                           ______________________________________                                         Medium: Wellcotest ® sensitivity test agar plus 7% lysed horse blood.

Antibacterial Screening

Antibacteial testing against Mycoplasma smegmatis (S3264) andStreptococcus pyogenes (CN10) was done with slight modifications usingstandard agar dilution assays as outlined in Manual of ClinicalMicrobiology Second Ed., E. H. Lennette. E. H. Spaulding and J. P.Trauant Eds., American Society for Microbiology, Washington, DC, 1974.

EXAMPLE 29

                  TABLE IX                                                        ______________________________________                                        Results of Antibacterial Testing Against Streptococcus pyogenes               (CN10)                                                                               Compound of                                                                            MIC                                                                  Example No.                                                                            (mg/L)                                                        ______________________________________                                               1B       ≦10                                                           2        10                                                                   3        10                                                                   6G       10                                                                   16       10                                                                   18B      ≦3                                                     ______________________________________                                    

EXAMPLE 30 Mycoplasma smegmatis Test

                  TABLE X                                                         ______________________________________                                        Results of Antibacterial Screening Against Mycoplasma smegmatis               (53264)                                                                              Compound of                                                                            MIC                                                                  Example No.                                                                            (mg/L)                                                        ______________________________________                                               1B       ≦10                                                           2        10                                                                   3        >100                                                                 6G       ≦3                                                            16       10                                                                   18B      10                                                            ______________________________________                                    

EXAMPLE 31 LD₅₀ Tests

                  TABLE XIV                                                       ______________________________________                                        LD.sub.50 Values for Selected Compounds                                       (IP single dose-CD-1 Male Mouse)                                                     Compound of                                                                            LD.sub.50                                                            Example No.                                                                            (mg/kg)                                                       ______________________________________                                               1B       140                                                           ______________________________________                                    

EXAMPLE 32 Formulation Examples

    ______________________________________                                        A. TABLET                                                                     ______________________________________                                        Compound of Formula I   500.0  mg                                             Pregelatinized Corn Starch                                                                            60.0   mg                                             Sodium Starch Glycolate 36.0   mg                                             Magnesium Stearate      4.0    mg                                             ______________________________________                                    

The compound of formula (I) is finely ground and intimately mixed withthe powdered excipients, pregelatinized corn starch and sodium starchglycolate. The powders are wetted with purified water to form granules.The granules are dried and mixed with the magnesium stearate. Theformulation is then compressed into tablets weighing approximately 600mg each.

    ______________________________________                                        B. TABLET                                                                     ______________________________________                                        Compound of formula (I) 500.0  mg                                             Corn Starch             70.0   mg                                             Lactose                 83.8   mg                                             Magnesium Stearate      4.2    mg                                             Polyvinylpyrrolidone    14.0   mg                                             Stearic Acid            28.0   mg                                             ______________________________________                                    

The compound of formula (I) is finely ground and intimately mixed withthe powdered excipients, corn starch and lactose. The powders are wettedwith a solution of polyvinylpyrrolidone dissolved in purified water anddenatured alcohol to form granules. The granules are dried and mixedwith the powdered stearic acid and magnesium stearate. the formulationis then compressed into tablets weighing approximately 700 mg each.

    ______________________________________                                        C. CAPSULES                                                                   ______________________________________                                        Compound of formula (I) 500.0  mg                                             Corn Starch             50.0   mg                                             Magnesium Stearate      3.0    mg                                             ______________________________________                                    

The finely divided compound of formula (I) is mixed with powdered cornstarch and wetted with denatured alcohol to densify the powder. Thedried powder is mixed with stearic acid and filled into hard-shellgelatin capsules.

    ______________________________________                                        D. SYRUP                                                                      ______________________________________                                        Compound of formula (I)                                                                              250.0   mg                                             Ethanol                250.0   mg                                             Glycerin               500.0   mg                                             Sucrose                3,500.0 mg                                             Flavoring Agent    q.s.                                                       Coloring Agent     q.s.                                                       Preserving Agent   0.1%                                                       Purified Water q.s. to 5.0     mL                                             ______________________________________                                    

The compound of formula (I) is dissolved in the ethanol, glycerin, and aportion of the purified water. The sucrose and preserving agent aredissolved in another portion of hot purified water, and then thecolouring agent is added and dissolved. The two solutions are mixed andcooled before the flavouring agent is added. Purified water is added tofinal volume. The resulting syrup is throughly mixed.

    ______________________________________                                        E. IV INJECTION                                                               ______________________________________                                        Compound of formula (I)                                                                         5.0 mg                                                      Glycerin          q.s. for isotonicity                                        Preservative      0.1%                                                        Hydrochloric Acid or                                                                            as needed for                                               Sodium Hydroxide  pH adjustment                                               Water for Injection                                                                             q.s. to 1 mL                                                ______________________________________                                    

The compound of formula (I) and preservative is added to the glycerinand a portion of the water for injection. The pH is adjusted withhydrochloric acid or sodium hydroxide. Water for injection is added tofinal volume and solution is complete after thorough mixing. Thesolution is sterilized by filtration through a 0.22 micrometer membranefilter and aseptically filled into sterile 10 mL ampules or vials.

What is claimed is:
 1. A pharmaceutical composition comprising acompound of formula (I)

    ArCH.sub.2 R.sup.1                                         (I)

wherein Ar is a chrysene ring optionally substituted by one or twosubstituents, said substituents containing not more than four carbonatoms in total when taken together, being the same or different and areselected from halogen; cyano; C₁₋₄ alkyl or C₁₋₄ alkoxy, each optionallysubstituted by hydroxy or C₁₋₂ alkoxy; halogen substituted C₁₋₂ alkyl orC₁₋₂ alkoxy; a group S(O)_(n) R² wherein n is an integer 0, 1 or 2 andr² is C₁₋₂ alkyl optionally substituted by hydroxy or C₁₋₂ alkoxy; orthe chrysene ring is optionally substituted by a group NR³ R⁴ containingnot more than 5 carbon atoms wherein R³ and R⁴ are the same or differentand each is a C₁₋₃ alkyl group; R¹ contains not more than eight carbonatoms and is a group ##STR11## wherein m is 0 or 1; R⁵ is hydrogen; R⁶and R⁷ are the same or different and each is hydrogen or C₁₋₃ alkyloptionally substituted by hydroxy; R⁸ and R⁹ are the same or differentand each is hydrogen or C₁₋₃ alkyl; ##STR12## is a five-or six-memberedsaturated carbocyclic ring; R¹⁰ is hydrogen, methyl or hydroxymethyl;R¹¹, R¹² and R¹³ are the same or different and each is hydrogen ormethyl; R¹⁴ is hydrogen, methyl, hydroxy, hydroxymethyl, a C₁₋₆alkylcarboxylic acid ester, or ether or a pharmaceutically acceptablesalt thereof, together with a pharmaceutically acceptable carriertherefor, except that the composition does not include the compound2-((6-chrysenylmethyl)amino-2-methyl-1,3-propanediol or apharmaceutically acceptable salt thereof.
 2. A composition of claim 1wherein Ar is 6-chrysenyl, ##STR13## wherein m is 0; R¹⁶ is CH₂ OH,CH(CH₃)OH or CH₂ CH₂ OH; R¹⁷ is hydrogen, C₁₋₃ alkyl or CH₂ OH; R¹⁸ ishydrogen or methyl; or a monomethyl or monoethyl ether thereofcontaining no more than 28 carbon atoms in total.
 3. A composition ofclaim 1 wherein R¹⁶ is CH₂ OH or CH(CH₃)OH and R¹⁷ is hydrogen, methyl,ethyl or CH₂ OH.
 4. A composition of claim 3 wherein R¹ is a diol of thestructure ##STR14## wherein R¹⁹ is hydrogen or methyl and R²⁰ ishydrogen, methyl or ethyl.
 5. A composition of claim 1 wherein acompound of formula I is selectedfrom:2-((6-Chrysenylmethyl)amino)-2-methyl-1-propanol,2-((3-Chrysenylmethyl)amino)-2-methyl-1,3-propanediol,2-((2-Chrysenylmetnyl)amino)-2-methyl-1,3-propanediol,2-((6-Chrysenylmethyl)amino)-2-hydroxymethyl-1,3-propanediol,(+-)(2R*,3R*)-2-((6-Chrysenylmethyl)amino)-2-methyl-1,3-butanediol,2-((6-Chrysenylmethyl)amino)-2-ethoxymethyl-1,3-propanediol,3-Methoxy-2-((6-chrysenylmethyl)amino)-2-methyl-1-propanol,(1α,2β,3α)-2-((6-Chrysenylmethyl)amino)-1,3-cyclohexanediol,2-((6-Chrysenylmethyl)amino)-2-isopropyl-1,3-propanediol,2-((6-Chrysenylmethyl)amino)-2-methyl-1,4-butanediol,(+-)(2R*,3RS*,4R*)-3-(6-Chrysenylmethyl)amino)-3-methyl-2,5-pentanediol,meso-3-((6-Chrysenylmethyl)amino)-2,4-pentanediol,2-((6-Chrysenylmethyl)amino)-1,3-propanediol,2(((12-Ethyl-6-chrysenyl)methyl)amino)-2-methyl-1,3-propanediol,2-(((12-Chloro-6-chrysenyl)methyl)amino)-2-methyl-1,3-propanediol,2-(((12-Ethoxy-6-chrysenyl)methyl)amino)-2-methyl-1,3-propanediol and(+-)(2R*,3S*)-2-((6-Chrysenylmethyl)amino)-2-methyl-1,3-butanediol
 6. Amethod of reducing the number of cells of a susceptible tumor comprisingcontacting the tumor cells with the composition of claim
 1. 7. Themethod of reducing the number of cells of a susceptible tumor comprisingcontacting the tumor cells with the composition of claim
 4. 8. Aninjectable preparation comprising the sterile composition of claim 1 ina pharmaceutically acceptable solvent.